Oxidative Stress and Gut-Derived Lipopolysaccharides in Neurodegenerative Disease: Role of NOX2
Lorenzo Loffredo, Evaristo Ettorre, Anna Maria Zicari, Maurizio Inghilleri, Cristina Nocella, Ludovica Perri, Alberto Spalice, C Fossati, Maria Caterina De Lucia, Fabio Pigozzi, Mauro Cacciafesta, Francesco Violi, Roberto Carnevale, Neurodegenerative Disease study group
Abstract
Background . Neurodegenerative diseases (ND) as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis represent a growing cause of disability in the developed countries. The underlying physiopathology is still unclear. Several lines of evidence suggest a role for oxidative stress and NADPH oxidase 2 (NOX2) in the neuropathological pathways that lead to ND. Furthermore, recent studies hypothesized a role for gut microbiota in the neuroinflammation; in particular, lipopolysaccharide (LPS) derived from Gram-negative bacteria in the gut is believed to play a role in causing ND by increase of oxidative stress and inflammation. The aim of this study was to assess NOX2 activity as well as serum 8-iso-prostaglandin F2 α (8-iso-PGF2 α ), serum H 2 O 2 , and LPS in patients with ND compared to controls. Methods . One hundred and twenty-eight consecutive subjects, including 64 ND patients and 64 controls (CT) matched for age and gender, were recruited. A cross-sectional study was performed to compare serum activity of soluble NOX2-dp (sNOX2-dp), blood levels of isoprostanes, serum H 2 O 2 , and LPS in these two groups. Serum zonulin was used to assess gut permeability. Results . Compared with CT, ND patients had higher values of sNOX2-dp, 8-iso-PGF2 α , H 2 O 2 , and LPS. Simple linear regression analysis showed that sNOX2-dp was significantly correlated with serum LPS (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mtext>Rs</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.441</mml:mn></mml:math>; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.001</mml:mn></mml:math>), zonulin (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mtext>Rs</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.411</mml:mn></mml:math>; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.001</mml:mn></mml:math>), serum H 2 O 2 (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"><mml:mtext>Rs</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.329</mml:mn></mml:math>; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M6"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.001</mml:mn></mml:math>), and 8-iso-PGF2 α (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M7"><mml:mtext>Rs</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.244</mml:mn></mml:math>; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M8"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.006</mml:mn></mml:math>). LPS significantly correlated with serum zonulin (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M9"><mml:mtext>Rs</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.818</mml:mn></mml:math>; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M10"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.001</mml:mn></mml:math>) and 8-iso-PGF2 α (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M11"><mml:mtext>Rs</mml:mtext><mml:mo>=</mml:mo><mml:mn>0.280</mml:mn></mml:math>; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M12"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.001</mml:mn></mml:math>). A multiple linear regression analysis was performed to define the independent predictors of sNOX2-dp. LPS (SE, 0.165; standardized coefficient β , 0.459; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M13"><mml:mi>p</mml:mi><mml:mo><</mml:mo><mml:mn>0.001</mml:mn></mml:math>) and 8-iso-PGF2 α (SE, 0.018; standardized coefficient β , 0.220; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M14"><mml:mi>p</mml:mi><mml:mo>=</mml:mo><mml:mn>0.005</mml:mn></mml:math>) emerged as the only independent predictive variables associated with sNOX2-dp (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M15"><mml:msup><mml:mrow><mml:mi>R</mml:mi></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow></mml:msup><mml:mo>=</mml:mo><mml:mn>57</mml:mn><mml:mi>%</mml:mi></mml:math>). Conclusion . This study provides the first report attesting that patients with ND have high NOX2 activation that could be potentially implicated in the process of neuroinflammation.